Atrial fibrillation is the most

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Review Articles

Treatment of new-onset atrial fibrillation in noncardiac intensive care

unit patients: A systematic review of randomized controlled trials*

Salmaan Kanji, PharmD; Robert Stewart, MD; Dean A. Fergusson, MHA, PhD;

Lauralyn McIntyre, MD, MSc, FRCPC; Alexis F. Turgeon, MD, MSc, FRCPC;

Paul C. Hébert, MD, MSc, FRCPC

A

trial fibrillation is the most common dysrhythmia among intensive care unit (ICU) adult patients (1, 2). In the critically ill surgical population, new-onset atrial fibrillation is most common after cardiac surgery (10 – 65%) (3), followed by tho-racic surgery (10 –23%) (4 –11), and

nonthoracic surgery (5–10%) (1, 12– 14). In the critically ill medical popula-tion, the prevalence of new-onset atrial fibrillation appears to range from 10 to 20% (15–17).

A relationship between new-onset atrial fibrillation and morbidity/mortality has been described in the critically ill patient. Following cardiac surgery, the development of atrial fibrillation is asso-ciated with a 2- to 2.5-fold increase in the risk of death in hospital and at 6 months, while this risk has been reported to be two- to six-fold higher after noncardiac surgery (1, 6, 11, 14, 18). Only one single-center study reports a doubling of the risk of death in medical ICU patients who develop new-onset atrial fibrillation (15). While this association between new-onset atrial fibrillation in the ICU and mortality has not been well described, it has been suggested that atrial fibrillation may

sim-ply be a marker of severity of illness rather than an independent contributor of mortality.

In most cases, atrial fibrillation is a transient phenomenon with a reversible underlying cause (i.e., electrolyte distur-bances, dramatic fluid shifts, hyperadren-ergic states, etc.). However, the underly-ing cause may often be multifactorial and not immediately reversible in a critically ill population. The efficacy of pharmaco-logic prophylaxis and treatment of atrial fibrillation after cardiac surgery has been evaluated in many studies leading to the recent publication of clinical practice guidelines in this population (19, 20). On the other hand, optimal treatment of atrial fibrillation in medical and (noncar-diac) surgical ICU populations is ill-defined despite a prevalence and morbid-ity similar to those of the cardiac surgery population. The objective of this project *See also p. 1681.

From the Ottawa Hospital (SK, LM, AFT, PCH), Ottawa, Canada; the Ottawa Health Research Institute (SK, DAF, LM, AFT, PCH), Ottawa, Canada; the Univer-sity of Ottawa (SK), Ottawa, Canada; the UniverUniver-sity of Montreal (SK), Montreal, Canada; and the QEII Health Sciences Center (RS), Halifax, Canada.

The authors have not disclosed any potential con-flicts of interest.

For information regarding this article, E-mail: skanji@ottawahospital.on.ca

Copyright © 2008 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

DOI: 10.1097/CCM.0b013e3181709e43

Objective:Atrial fibrillation is a common problem associated with morbidity and mortality in critically ill patients; however, evidence-based treatment recommendations are lacking. The ob-jective of this systematic review was to evaluate the efficacy of pharmacologic rhythm control of new-onset atrial fibrillation in noncardiac, critically ill adults.

Data Source:Citations identified from an electronic search of Medline, the Cochrane register of controlled trials, and Embase databases (1966 to August 2006) were independently reviewed by two investigators.

Study Selection: All prospective randomized controlled trials evaluating pharmacologic rhythm conversion regimens for new-onset atrial fibrillation in (noncardiac surgery) critically ill adult patients were included. The primary end point was atrial fibrilla-tion resolufibrilla-tion.

Data Extraction: Using a standardized data extraction form, data related to study design, population characteristics, pharma-cologic intervention, and outcome measures were collected.

Data Synthesis: Four trials met inclusion criteria from 1995 citations screened. Of the 143 evaluable patients in these trials 89

(76%) had atrial fibrillation while the remaining ones had other atrial tachyarrhythmias. Drugs evaluated for rhythm conversion included amiodarone (n26), procainamide (n14), magne-sium (n18), flecainide (n15), esmolol (n28), verapamil (n15), and diltiazem (n27). The definition of treatment success ranged from conversion within 1 hr to conversion within 24 hrs. No study evaluated maintenance of conversion, and one study included hemodynamically unstable patients. Lack of meth-odologic homogeneity prevented any pooled analysis.

Conclusions:Using the current published literature, we cannot recommend a standard treatment for atrial fibrillation in noncar-diac critically ill adult patients. Clinical trials evaluating rhythm conversion in critically ill populations outside of cardiac surgery are lacking. Further trials that address goals of care in hemody-namically stable and unstable patients and utilize standardized definitions of successful cardioversion are required. (Crit Care Med 2008; 36:1620–1624)

KEY WORDS: atrial fibrillation; supraventricular arrhythmia; in-tensive care; critical care; systematic review

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was to evaluate the existing evidence for pharmacologic rhythm conversion for new-onset atrial fibrillation in noncardiac critically ill adults. Therefore, we con-ducted a systematic review of published clinical trials comparing the effect of drug treatment regimens in this population.

METHODS

Search Strategy.We conducted a system-atic search of Medline, Cochrane, and Embase databases from 1966 until August 2006 to identify randomized controlled trials evaluat-ing the effect of pharmacologic treatment of new-onset atrial fibrillation in critically ill pa-tients. Only peer-reviewed trials published in English language were considered eligible for this review. Databases were searched using a combination of the following terms: “atrial fibrillation,” “atrial flutter,” “supraventricular arrhythmia,” “tachyarrhythmia,” “critical care,” and “intensive care” with the Dickersin filter for randomized controlled trials (21). The search also incorporated text words for drugs including “disopyramide,” “procain-amide,” “quinidine,” “lidocaine,” “mexilitine,” “phenytoin,” “tocainide,” “flecainide,” “mori-cizine,” “propafenone,” “amiodarone,” “so-talol,” “ibutilide,” “dofetilide,” “bretylium,” “esmolol,” “propranolol,” “metoprolol,” “dilti-azem,” and “verapamil.” Reference lists of re-view articles and included studies were also screened for additional studies. Two experi-enced practitioners (SK and RS) indepen-dently reviewed all citations retrieved from the electronic search to identify potentially rele-vant trials.

Study Selection.All randomized controlled trials comparing a pharmacologic therapy to an inert or an active control for new-onset atrial fibrillation in critically ill adult patients were included in this systematic review. New-onset atrial tachyarrhythmias were defined as atrial fibrillation, atrial flutter, or other su-praventricular tachyarrhythmias of less than 7 days duration. Continuous electrocardiogra-phy monitoring was required during the study period. Patients had to be critically ill, defined as being admitted to an ICU, and be more than 16 yrs of age. Studies in cardiac surgery patients or on patients treated before ICU admission were excluded. The primary outcome measure was rhythm conversion to normal sinus rhythm of any duration.

Data Extraction and Validity Assessment. Using a standardized data extraction form, data related to study design, population charac-teristics, pharmacologic intervention, and out-come measures were collected. Discrepancies of data interpretation were resolved by consensus among investigators. Attempts were also made to acquire additional information from study investigators when possible. Quality assessment of each study was conducted using the rating instrument developed by Jadad et al (22). This

instrument evaluates clinical trial integrity based on methods of randomization, blinding and documentation of withdrawals from the study. Scores for each section of the instrument were determined and reported individually. A maximum score of 5 would be awarded to a trial with the greatest methodologic integrity (i.e., appropriately described randomization

proce-dure and double blinding with description of withdrawals from the study). We considered tri-als with a score of 3 or higher to be of high-methodologic quality.

Data Synthesis.Data related to study de-sign, drug treatment, patient demographics, and outcome measures including conversion rates as defined by the trials, time to

conver-1995 Citations screened 44 RCTs retrieved for detailed evaluation 4 RCTs included 40 articles excluded 13 post-op cvs surgery 4 prospective cohort studies 12 not acute-onset AF 10 not critically ill patients 1 review article

Figure 1.Clinical trial screening.RCT, randomized controlled trial;AF, atrial fibrillation.

Figure 2.Conversion rates (and 95% confidence intervals) for all drugs evaluated. Conversion rates reported as percent with 95% confidence intervals for reported conversion rates at 12 hours for each drug except flecainide and verapamil, which are presented as 1-hour conversion rates.

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sion, arrhythmia recurrence rates, and adverse events were described for individual studies identified. Pooled estimates of outcome mea-sures were not calculated due to study heter-ogeneity, therefore, forest plots without pooled estimates are presented.

RESULTS

Search Results and Description of Stud-ies.From 1995 citations screened, 44 were evaluated and four trials (n ⫽143) were included in the analysis (23–26). (Fig. 1). Two trials included a mixed population of surgical and medical patients (25, 26) while the remaining two were performed in a strict medical population (24) and a surgi-cal population (23). While all studies ex-cluded patients after cardiac surgery, one trial included three patients thoracot-omy (26) and one enrolled 15 patients post-thoracic surgery (23). Of the 143 evaluable patients, 89 (76%) had atrial fibrillation while the remaining had other atrial tachy-arrhythmias. All trials evaluated the cess of cardioversion. The definition of suc-cess ranged from rhythm conversion within 1 hr to conversion within 24 hrs (Table 1). The antiarrhythmic drugs evalu-ated included amiodarone (two trials, n⫽ 26), procainamide (one trial, n⫽14), mag-nesium (one trial, n⫽18), and flecainide (one trial, n ⫽15), while the chronolytic drugs evaluated include esmolol (one trial, n⫽28), verapamil (one trial, n⫽15), and diltiazem (one trial, n ⫽ 27). One trial included hemodynamically unstable pa-tients (23).

Methodologic Quality. One trial was considered to be of high methodologic quality (26). All trials were randomized

comparator control trials; however, only one trial described an appropriate method of randomization (26). None of the trials were blinded. One trial (23) described an intention-to-treat analysis and no trial col-lected data beyond 24 hrs, thus no patients were lost to follow-up.

Outcomes. Rhythm conversion was defined by a different metric in each trial ranging from conversion within 1 hr to conversion within 24 hrs. Maintenance of rhythm control was not evaluated in any study. The two studies that evaluated rhythm conversion with amiodarone re-ported success rates of 50 –70% at 12 hrs and 50% at 24 hrs (25, 26). Chapman et al. observed similar success rates of ami-odarone use when compared to procain-amide (70 vs. 71% at 12 hrs for amioda-rone and procainamide, respectively;p⫽ not significant) (25). Moran et al. re-ported a higher conversion rate with magnesium at 24 hrs (77%) when com-pared to amiodarone (50%, p value not reported) (26). Most patients in these two trials also received digoxin for rate con-trol purposes. In the study by Barranco et al., the primary outcome of conversion to normal sinus rhythm within 1 hr oc-curred in 80% of patients receiving fle-cainide and 33% of those receiving vera-pamil (p .001) (24). The authors concluded that flecainide was an effective agent for the conversion of atrial tachy-arrhythmias to normal sinus rhythm. Fi-nally, the study by Balser et al. compared the frequency of rhythm conversion within 12 hrs between two pharmaco-logic interventions (diltiazem and esmo-lol) traditionally considered as rate

con-trol agents (23). Conversion rates with esmolol were higher than those of dilti-azem at 2 hrs (68% vs. 33%,p⬍.05) and at 12 hrs (85% vs. 62%,p⫽.116). Both agents were equally effective for rate con-trol of rapid atrial arrhythmias. Conver-sion rates are summarized in Figure 2.

Safety was evaluated in all studies. Among the 24 patients randomized to receive amiodarone, two patients experi-enced clinically significant hypotension and two others died before trial comple-tion. The cause of death in these two patients was not described by the au-thors. Treatment with flecainide (n⫽15) was associated with a significant prolon-gation of the QRS interval resulting in frequent premature ventricular contrac-tions in one patient and brief episodes of hypotension in two patients, none of which required interruption of the infu-sion. Hypotension was observed in three patients treated with verapamil (n⫽15), ten patients treated with esmolol (n ⫽ 34) and 12 patients treated with diltiazem (n ⫽ 30). Hypotension was most often observed during the loading dose and was self-limited. Discontinuation of the study drug was only necessary in two patients receiving esmolol and one patient receiv-ing diltiazem.

DISCUSSION

This systematic review of clinical trials evaluating the effect of pharmacologic treatment on rhythm conversion of new-onset atrial fibrillation in noncardiac crit-ically ill patients yielded only four trials of which 89 subjects enrolled had atrial Table 1. Study characteristics

Trial Design Blinding Patients N Intervention

Patients with AF Definition of Cardioversion Chapman (1993) Randomized comparator controlled

No Med/surg 24 Amiodarone (3 mg/kg bolus then 10 mg/kg over 24 hrs) vs. procainamide (10 mg/kg bolus then 4 mg/min⫻2 hrs, then 3 mg/kg⫻2 hrs then 2 mg/kg⫻20 hrs) 16/24 Within 12 hrs Moran (1995) Randomized comparator controlled

No Med/surg 42 (34 evaluable) Amiodarone (5 mg/kg bolus then 10 mg/kg over 24 hrs) vs. magnesium (37 mg/kg bolus, then 25 mg/kg/hr⫻24 hrs) 18/34 Within 24 hrs Barranco (1994) Randomized comparator controlled

No Med 30 Flecainide (2 mg/kg bolus then 1.5 mg/kg over 1 hr) vs. verapamil (0.15 mg/kg bolus then 0.005 mg/kg/min⫻1 hr)

11/30 Within 1 hr Balzer (1998) Randomized comparator controlled

No Surg 55 Esmolol (12.5–50 mg repeated bolus until HR⬍110 beats/min then 50–100␮g/ min) vs. diltiazem (20 mg bolus then 10–20 mg/hr)

44/55 Within 12 hrs

Total 143 89/143 (76%)

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fibrillation. While all the trials identified evaluated rhythm conversion as their pri-mary outcome measure, considerable heterogeneity related to patient selection, definitions of outcome measures, and du-ration of study was observed, limiting our ability to make a generalizable statement about pharmacologic rhythm conversion in this population. Little evidence exists that describes superior efficacy of one drug over another or even one drug over placebo. Thus, based on the current lit-erature, we cannot recommend evidence-based standards regarding both goals of treatment and intervention selection in critically ill adult patients with new onset atrial fibrillation.

A comparable systematic review was recently conducted evaluating pharmaco-logic rhythm conversion of atrial fibrilla-tion after cardiac surgery (19). This re-view identified 19 randomized controlled trials evaluating a variety of antiarrhyth-mic drugs. Similar limitations of the in-cluded trials were identified by the au-thors including heterogeneity between trials with respect to study subjects, out-come measures, and monitoring meth-ods. Due to this heterogeneity and subse-quent highly variable conversion rates, no pharmacologic strategy was identified as su-perior to another. For comparison, conver-sion rates were 13 to 100% in four trials of amiodarone, 51 to 93% in two trials of pro-cainamide, 86 to 93% in two trials of flecainide, and 7 to 55% in two trials of diltiazem. Of note, two trials reported conversion rates of 24 and 16% for pla-cebo. Conversion rates for the common drugs in the current systematic review were at least similar to conversion rates reported in the cardiac surgery system-atic review.

In comparison, direct current cardio-version may be an attractive alternative to pharmacologic rhythm control. This is especially true for the patient with new-onset atrial fibrillation and deteriorating hemodynamics where prompt restoration of sinus rhythm is essential and avoiding pharmacologic exacerbation of hypoten-sion is pivotal. In noncritically ill patients direct current cardioversion has been de-scribed as a highly effective therapy with rates of successful restoration of normal sinus rhythm as high as 70 to 95% (27– 29). However, only one prospective obser-vational study of monophasic direct cur-rent cardioversion in 37 surgical ICU patients reports a successful initial con-version rate of 35% and only 13.5% at 48 hrs (30).

Considering the prevalence of atrial arrhythmias in the noncardiac critically ill patient and the associated morbidity and mortality, there are very few prospec-tive randomized trials designed to evalu-ate the treatment of this condition. One reason that could explain the paucity of research in this area is the difficulty in conducting clinical trials in these pa-tients. Because new-onset atrial fibrilla-tion with a rapid ventricular rate is con-sidered an emergency, enrolling these patients into clinical trials is logistically difficult as rapid intervention may be de-sired.

The limitations of this systematic re-view are related to the included primary studies. Differences in the baseline study populations might have lead to different treatment effects since all studies in-cluded subjects with a variety of atrial arrhythmias. While cardiac surgery pa-tients were excluded, two trials enrolled thoracic surgery patients. Furthermore, three of the four clinical trials excluded patients who were hemodynamically un-stable. Grouping atrial fibrillation with atrial flutter and supraventricular tachy-cardias might also be inappropriate as the primary physiology behind them and their treatment response might be differ-ent (15). The study by Balser et al. was the only study to evaluate hemodynami-cally unstable patients. Given the poten-tial consequences of hemodynamic insta-bility in a critically ill patient, the goal of care in this population would be rhythm conversion presumably to restore the atrial kick and improve cardiac output. On the other hand, rhythm control might be unnecessary if rate control can be achieved while the underlying disease is managed. One could argue that if rate control is the goal of care, conversion without an antiarrhythmic agent would represent spontaneous conversion. How-ever, as hypothesized in the study by Balser et al., beta adrenergic blockade alone may have antiarrhythmic activity in the setting of adrenergic-induced atrial arrhythmogenicity.

The second major limitation of the studies included in this review relates to the lack of standardized outcome mea-sures. The definition of successful cardio-version ranged from concardio-version within one hour to conversion within 24 hrs, but no study evaluated maintenance of con-version. Since the etiology of atrial fibril-lation in the critical care setting is often attributed to reversible causes that may not be immediately corrected, many

pa-tients will relapse into atrial fibrillation after presumably successful rhythm con-version. Such discrepancy in the defini-tion of the primary outcome prevents any recommendation on treatment efficacy. Moreover, from the trials evaluated in this systematic review it is impossible to differentiate drug efficacy from spontane-ous conversion. A standardized definition of rhythm conversion that incorporates a means to evaluate maintenance of nor-mal sinus rhythm after conversion would be needed for further trials.

In summary, well-designed random-ized controlled trials evaluating rhythm conversion in critically ill adult patients outside of cardiac surgery care are lack-ing. Only four prospective studies were identified and their interpretation was limited by considerable methodologic heterogeneity. While antiarrhythmic agents such as amiodarone, magnesium, procainamide, and flecainide are all scribed as effective agents to varying de-grees, it is difficult to differentiate the efficacy of the drug from spontaneous conversion. Future studies should ad-dress treatments of choice and goals of care using a standardized outcome mea-sure of success. Properly designed, ade-quately powered prospective clinical tri-als are required.

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